The role of inflammation in allergic diseases, especially in asthma is widely recognized, and inflammation of the airways is one of the three major characteristics of asthma1;2. The major infiltrating effector cells in asthma contributing to the inflammatory response are eosinophils, mast cells and Th2 lymphocytes3-5 all contributing to a complex pathologic process that ultimately leads to reduced lung function.
The molecular mechanisms involved in the recruitment of these cells from the circulation are complex6, Chemokines are of fundamental importance in this multistep process. Being present on the endothelium bound to glycosminoglycans, chemokines trigger integrin activation on rolling leukocytes resulting in their firm adhesion on the endothelial surface7. Transendothelial migration of the leukocytes into the surrounding tissue also strongly depends on chemokines and their receptors8. Key molecules involved in asthma belonging to the chemokine system have been recently elucidated. CCL11 (eotaxin) was the first specific chemokine identified as an attractant for eosinophils in the bronchoalveolar lavage fluid (BALF) obtained from an experimental model of allergen exposure of sensitized guinea pigs9 and was subsequently shown to be present in humans10. The functionally related chemokines CCL24 (eotaxin-2) and CCL26 (eotaxin-3) were described thereafter11;12 Besides the eotaxins, the MCPs, CCL5 (RANTES) and a truncated chemokine derived from CCL14 (HCC-1) are attracting the same type of inflammatory cells being involved in asthma13;14. An important role of CCL11 for the attraction of eosinophils into the lung was recently shown by several groups in human asthmatic subjects. The influx of eosinophils correlates strongly with increased peptide and mRNA expression of CCL1115;16.
The common feature of the eotaxins, the MCPs and CCL5 are their ability to mediate chemotaxis via the chemokine receptor CCR3, which has been shown to be expressed on eosinophils17, mast cells18, basophils19, and Th2-cells20;21. The involvement of other chemokines was clearly demonstrated in vivo showing that different chemokines, in the majority activators of CCR3, contribute at different levels to the complex pathophysiology of asthma22. Only this year a major breakthrough for the extraordinary role of CCR3 in asthma was achieved. Targeted disruption of CCR3 was successfully performed showing that eosinophils and other inflammatory cells were arrested in the subendothelial space of pulmonary vessels after bronchial allergen challenge in OVA-sensitized mice23, implicating that the local inflammatory response can be abolished targeting CCR3 already in the circulation. Furthermore airway hyperresponsiveness (AHR) is completely abrogated in CCR3-deficient mice in which the animals are sensitized by the epicutaneous route24. Therefore the common receptor CCR3 is exceptionally attractive as a drug target, and its blockade is already propagated as a therapy for asthma25.
CCL14 was recently isolated from human hemofiltrate based on its high concentrations in human blood plasma26. The originally isolated molecular form of CCL14 containing 74 amino acid residues was shown to be a very weak activator of monocytes. Later on, chemically synthesized N-terminal truncated forms of CCL14 were shown to be more potent activators of monocytes acting via CCR127. Further screening of human hemofiltrate fractions for novel natural ligands of chemokine receptors led to the identification of the variant CCL-14[9-74], being a potent agonist for CCR1, CCR3, and CCR528.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill in the art from the following description. It should be understood, however, that the following description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following description and from reading the other parts of the present disclosure.